This study compares the efficacy of two drugs, TCT and ABA, for treating schizophrenia in 22 treatment- resistant patients. It involves an initial placebo "washout" period that withdraws patients' standard treatments for 2 weeks, raising risks. Additionally, informed consent may be challenging given patients' vulnerability and the technical nature of the consent form. The REB must decide whether to approve the study as is or require changes given its duties to protect participants and ensure ethical standards are met.

1. ETCR 120 Ethical case analysis #1 Xiomara Arias Fernandez
ETRC 120 October 7 2012
Michener Institute
ETCR 120
Efficacy of TCT and ABA in 22 hospitalized treatment-resistant patients with
Schizophrenia: A comparative study
Clinical Case Analysis
(Modules 3 and 4)
Xiomara Arias Fernández

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Efficacy of TCT and ABA in 22 hospitalized treatment-resistant patients with Schizophrenia: A
comparative study
Introduction: Relevant facts
This study attempts to help resolve a controversy regarding which of two treatments is better for
treating schizophrenia. It is part of a 22-site multicenter US and Canada study and the Western
Canada University Research Ethics Board (WCU REB) is responsible for reviewing and
approve/disapprove this study .(The original description of the assignment is given at the end of this
paper under the references section).
This paper evaluates the clinical study proposed with reference to relevant moral codes and
guidelines, identifying the main moral concerns in order to suggest changes that would minimize these
moral issues and their implications for the wellbeing of participants involved in the study.
One of the relevant facts that arise in this study is primarily related to the use of a placebo “wash
out”. In fact, a placebo run-in period is seen as a potential harm that could negatively affect the
wellbeing of the participant and the safety of others. Risk/benefit ratio should be heavily considered.
Another relevant fact in this study has to do with informed consent performance. These
participants belong to a vulnerable group since they suffer from mental illness. Without adequate
treatment, while performing the study, symptoms of schizophrenia could worsen to the point that
participants may become unable to give their informed consent.
A final fact that could raise ethical concerns is the criterion of inclusion/exclusion of potential
participants.
In regards to the investigator duties and participant rights, firstly, participants have the right not to
be harmed by any procedure involved in the study, and to receive adequate medical care for any
adverse event that occurs. For instance, participants must be given the best possible medical

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treatments available in the market when side effects arise from the drugs taken as part of the clinical
trial. It is the investigator’s duty to provide this protection for all subjects. Essentially, according to the
Harmonized Tripartite Guideline (ICH) 1(p 9): “The Independent Ethics Committee (IEC) has the
obligation to protect the rights, safety and well being of all the subjects involved in a trial”. IEC must
enforce a good communication among all the parts involved in the trial. According to Helsinki principle
(²) section B, 1 (p 2): “Physicians in Medical research have the duty to protect life, health, privacy and
dignity of the subject who participate in a trial.”
Secondly, there is a personal and moral duty of the sponsor, investigators and the participant’s
legal representative (if one is needed) to ensure that genuine informed consent is fully accomplished.
As mentioned at the introduction of this paper, investigators have an obligation to estimate the
risk/benefit ratio to minimize any harm to participants. One of the main duties of The investigator(s) is
to design the study in a way that optimize the potential to acquire meaningful results from the study
while minimizing risk.
As it mentioned in the introduction, one of the moral issues is that there is a risk that the
participants of the study become unable to continuing given genuine consent .If this situation happen
they must be excluded from the study. However, since they belong to a vulnerable population they
should not be excluded because they have the right to obtain benefits from the study and part of the
criteria of inclusion of the study that states that participants must suffer of the active disease in study.
The use of a placebo raises a moral issue in the study, because this may breach the researcher’s
duty to minimize harm to the participants. It is unethical to enroll participants in a study .when it may be
expected that their medical condition(s) will worsen.
Another moral issue is related to the potential occurrence of adverse events, and raise a question:
What standard of care should be provided to the participants who become ill during the study, whether

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as a consequence of using the new drug or as a result of the primary treatment withdrawal?
A final issue is the possibility that some individuals who belongs to a vulnerable group (i.e., pregnant
women) could be inappropriately excluded from the research and thus be denied of a potential benefit
from the study
In relation with the changes to be considered in this case, first, there must be complete disclosure
of the risks - this is required in order for informed consent to be meaningful. Full disclosure is
mentioned in article 3.2 (p30) of The Tri-council Policy Statement (TCPS)(3 ). Second, because of the
risk regarding participants’ health and safety, the use of a placebo in this study contravenes the
Helsinki (²) and the non-maleficence (4) principle. The participant must be fully informed in detail about
the purpose of the trial to avoid the assumption that they will receive health benefits from participating,
when in reality they will be kept from taking any beneficial drug during the placebo run. Further,
participants’ level of risk is high since the benefits of the trial drug have not yet been proven. In this
regard, the declaration of Helsinki (²) in section 3, 17-20(p 23) emphatically states that “Medical
research is only justified if ... the populations benefit from the results of the research”. Based on the
TCPS 3 core principles and article 3.1, (p 28) and on Belmont (5) principle of respect for persons and their
autonomy, it would be necessary to ensure that participants be able to give informed consent
throughout the duration of the study, and/or allow the subjects to potentially withdraw from the study if
necessary, without undermining their wellbeing. Since the core of the consent process is to clearly and
precisely inform of the trial process as a whole and also to protect the participants, they need to
understand the purpose and the potential consequences of the study thoroughly, not only at the
beginning of the process but also during the investigation itself by monitoring consent. Although this
obligation seems difficult to accomplish since participants could be argued to have limited
understanding of technical and scientific terminology, this shouldn’t be a problem, since according to
Section 2.2 of The Nuffield Council of Bio Ethics 6 (p 11) “Researchers must do their best to
communicate information accurately

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and in an intelligible and appropriate way, taking in account of local knowledge and beliefs” .
Supplementary documentation should be available for use according to every particular case, including
those in which participants’ lack of technical knowledge about the informed consent could pose a
problem. In these instances, rather than ask the subjects to sign the forms, it may be more appropriate
to have a witness (e.g., a relative) who verbally agrees with the investigation and its procedures.
Further, misunderstandings can be remedied by ensuring that genuine consent is given, and that lack
of consent is eliminated. This seems to be particularly important if any of the participants lose capacity
to give consent during the course of the trial due to worsening of their schizophrenia.
On the other hand, and although it is expected that there would be at least one member with
documented expertise in the WCU REB to understand the study technical definitions, it may be suitable
to provide training to all members who are relatively new, such as Ms. Jeffrey, who doesn’t have the
expertise to understand the study terminology used in the consent.
Based on the Belmont principle (5) of Beneficence, the Utilitarian Ethical Theory (7) and also on
the US Federal Code Regulations (CFR) 8 title 45, 46.111(1, 2, b), it would be necessary to assess the
projection of study benefits in terms of medical advancements (risk/benefit ratio). Furthermore beside
this, adequate medical care should planned ahead to be given to the trial participants who eventually
can result injured by any procedure in the study and additional safeguards must be provided.
Based on the Belmont principle (5) of Justice and TCPS (3) guidelines it would be necessary to
evaluate the reason(s) why pregnant women are excluded from this study. According to TCPS 3 (p 49)
Article 4.3: “Women shall not be inappropriately excluded from research ... because...they are
pregnant...Exclusions should be made on the basis of clear criteria...”.Also CFR (8) title 45, 46.111(3)
provide that selection of the subject participant must be equitable, being especially cognizable about
vulnerable population such as pregnant women.
Finally, if perceived risk to participants is too great, and the study has not been adequately
designed to minimize these risks, the study may not be ethically acceptable. In such cases it may be

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possible to reconsider the research question and look for another design that fulfills the ethical
requirements .( According to The CFR 8 in 46.112 , WCU REB would be in capacity to make further
reviews of the study and may approve/disapprove it. )WCU REB in accordance with IHC guidelines ¹
(pp11, 12) 3.3.7 and 3.3.8 (a) should approve any appropriate amendment and maintain continuous
communication between investigators in order to ensure that participants’ wellbeing is protected,
complying also with Helsinki(2) declaration, part B, 13 .All the criteria appointed by CFR( 8) in section
46.111 must be analyzed by the WCU REB at the time of approve this study, particularly exerting
cooperative research as expressed by the CFR( 8 ) in section 46.114.

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References
(¹) International conference on harmonisation of technical requirements for registration of
pharmaceuticals for human use. ICH Harmonised tripartite guideline validation of analytical procedures:
Text and Methodology Q2 27 October 1994 (Complementary Guideline on Methodology dated 6
November 1996 incorporated in November 2005)
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q2_R1/Step4/Q2_R1_
_Guideline.pdf
(²) World Medical Association Declaration of Helsinki Ethical Principles for Medical Research Involving
Human Subjects (p4, Section C, 29). Additional principles for medical research combined with medical
care. At http://www.fda.gov/ohrms/dockets/dockets/06d0331/06D-0331-EC20-Attach-1.pdf
(3) Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of
Canada, and Social Sciences and Humanities Research Council of Canada, Tri-Council Policy
Statement. Ethical Conduct for Research Involving Humans, (Chapter 1 (pp8, 10) Chapter3 (pp 27- 45)
December 2010
At http://www.pre.ethics.gc.ca/pdf/eng/tcps2/TCPS_2_FINAL_Web.pdf
(4) Omonzejele, P. F. Obligation of non-maleficence: moral dilemma in physician-patient relationship (p
23) JMBR: A Peer-review Journal of Biomedical Sciences Vol. 4 No.1 pp-22-30; June 2005
At http://www.bioline.org.br/pdf?jm05003
(5). Gov. U.S Department of Health and Human Services (HHS). The Belmont Report. April 18,
1979.(Internet September 2012)
Athttp://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html

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(6) The Nuffield Council of Bio Ethics. Research related in Developed countries. Chapter 2
Consent.(p11);2002 At
http://www.nuffieldbioethics.org/sites/default/files/files/HRRDC%20Follow%20up%20Chapter%202%20
-%20Consent.pdf
(7) Beauchamp t, Bowie N., Arnol, D.Ethical Theory and business 8th
Ed. Normative ethical theories.
Utilitarian theories (p 18) Lavosier; 1995
8) The US Federal Cod Title p45 Public Welfare, Part 46 Protection of Human Subjects At
http://ecfr.gpoaccess.gov/cgi/t/text/textidx?c=ecfr&sid=cda3365ad224bf252867e02264d67e71&rgn=div
8&view=text&node=45:1.0.1.1.25.1.1.9&idno=45

9. ETCR 120 Ethical case analysis #1 Xiomara Arias Fernandez
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Ethical case analysis
Cynthia Jeffrey is a new member of the University of Western Canada's research ethics Board (REB).
Her orientation session to the new Tri-Council Policy Statement and to the REB's responsibilities
seemed straightforward, but as she considers the most recent proposal on the REB's agenda, she
knows that they face a difficult decision. The proposal from Dr. Cecil Tan, a senior researcher in the
department of Psychiatry, appears to contravene some sections of the Policy Statement. However, the
study is part of a 22-site multicentre US and Canada study sponsored by a major international
pharmaceutical firm and cannot be modified for UWC alone; the REB appears to have the choice of
accepting it without change or forcing Dr. Tan to withdraw from the study.
The study is a clinical trial of TCT, a new drug for the treatment of Schizophrenia. The study will
compare the efficacy of TCT against that of ABA, a widely used antipsychotic drug, on hospitalized
treatment resistant patients. 22 subjects from a nearby hospital are to be selected according to strict
criteria defining the activity and duration of their schizophrenia, with exclusions for pregnant women and
other contraindicated conditions such as hypertension and known history of adverse reactions to
antipsychotic. Response to the ten-week treatment with TCT or ABA will be measured by scores on two
accepted psychiatric scales that will require blood analyses, ECGs, and other diagnostics throughout
the study.
Because 25% of schizophrenic patients have been shown to respond to placebos, the sponsor requires
an initial placebo run-in period (also known as "placebo washout") for all subjects to establish baseline
patient ratings without treatments. During the run-in, the medication of all subjects is to be discontinued
for two weeks and to be reinstated if severe problems arise. Dr. Tan has already been questioned
about the placebo run-in, but he and the sponsor argue that the standard treatments have potentially
serious side effects and the period of treatment withdrawal is short. Dr. Jeffrey is unsure whether
withholding standard treatments is unethical in this situation, particularly since the risk of subjects
harming themselves or others intensifies without treatment.
Although the rest of the REB has not yet considered it, she is also concerned about the ability of the
subjects to give free and informed consent to the research, given that a criterion for selection is their
hospitalization for at least one year with active schizophrenia. The consent form provided with the
proposal is long, quite technical, and difficult for her to understand, and she wonders whether a patient
suitable for the study could grasp its meaning and freely agree to the trial.
Discuss this case with reference to guidelines, policies and codes referred to in modules 3 and 4.